The statements in this section merely provide background information related to the present disclosure and may not constitute prior art.
Laminitis is a complex disease process in horses which includes inflammation of the sensitive lamina along the dorsal aspect of the foot, and results in detachment of the bone (distal phalanx) from the hoof wall with subsequent downward rotation or distal displacement of the bone (founder). Affected animals are often in severe pain, prone to recurrent episodes, and in many cases must be destroyed due to the permanent damage that occurs within the hoof. Numerous predisposing factors may contribute to the development of laminitis, but the pathogenesis remains undetermined.
Several theories have been proposed for the development of laminitis including the “vascular” hypothesis and the “toxic/metabolic” hypothesis. The vascular hypothesis suggests the primary problem exists in dysfunction of the digital vasculature resulting in digital tissue ischemia—any subsequent problem including metabolic dysplasia, inflammatory processes, and structural failure is due to the initial ischemic event. The toxic/metabolic hypothesis proposes “trigger factors” or toxins which directly damage the epidermal cells or basement membrane of the laminae resulting in tissue destruction while subsequent vascular, structural, and inflammatory changes are considered secondary to the damage caused by the toxins. The primary difference between the two theories is that the vascular theory involves reduced digital blood flow (ischemia) and the toxic/metabolic theory involves increased digital blood flow.
In general, laminitis is a local manifestation of a systemic disease. Affected horses, for example, often present with a gastrointestinal system event which contributes to the disease processes within the feet. A common scenario involves an animal that eats too much grain or lush pasture or develops a gastrointestinal tract infection. Gut fermentation is altered and the intestinal mucosal barrier is damaged resulting in absorption of toxins to the peripheral circulation. The toxins are theorized, as discussed above, to directly damage the laminae or to alter blood flow to the digit resulting in laminar ischemia.
Additional laminitis predisposing factors include grain overload, colitis, small intestinal strangulation/obstruction, proximal enteritis, metritis, pleuropneumonia, and any other condition involving septicemia or toxemia. Often, however, the true cause is unknown.
Bovine lactic acidosis results from diets high in ruminally available carbohydrates or forage too low in effective fiber, and is associated with large increases of lactic acid in the rumen. Clinical manifestations range from loss of appetite to death while laminitis is implicated physiologically. The challenge to the dairy industry is more often subclinical acidosis rather than acute acidosis. Subclinical acidosis is characterized by a decrease in pH with only very little accumulation of lactic acid in the rumen. Repeated episodes of pH<5.5 for given periods ultimately predispose cattle to low grade, subclinical acidosis, the symptoms of which include erratic appetite, weight loss, diarrhea, and lameness as a result of laminitis.
Laminitis is also a problem for mules, donkeys, sheep, pigs, goats, camels, and other hoofed animals.
Conventional treatment of laminitis varies depending on the perceived underlying cause. Initial treatment can involve intravenous fluid therapy, systemic antimicrobials, intravenous dimethyl sulfoxide, anti-inflammatory drugs, and administration of mineral oil with a nasogastric tube. Nonsteroidal anti-inflammatory drugs are used to decrease inflammation within the foot, and other drugs used to improve blood flow to the laminae of the affected foot. Unfortunately, standard treatments fail to consistently provide relief and prevent damage.
Regardless of the cause, laminitis results in damage and irreversible changes to the hoof, not to mention the extensive pain for the animal involved. The owner's cost of treatment and the expense involved in the loss of use of the animal are further challenges that need to be addressed.
The present invention is directed toward overcoming one or more of the problems discussed above.
British Patent Specification No 2,022,078 mentions a large number of pyranoquinolinone derivatives purportedly useful as prophylactic inhalation anti-asthmatics when administered as unit dosages of from 0.01 to 10 mg in admixture with coarse lactose. This patent specification also mentions the disodium salt of 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]-quinoline-2,8-dicarboxylic acid, which salt is commonly known as nedocromil sodium or TILADE™.
Against this backdrop the present disclosure is provided.